tbuckley/cabot-search huggingface dataset:
Anlotinib combined with transarterial chemoembolization for unresectable hepatocellular carcinoma associated with hepatitis B virus: A retrospective controlled study.
Authors: Wenbo Guo, Song Chen
Journal: Journal of Clinical Oncology (2023)

e16138 Background: Hepatocellular carcinoma (HCC) has the third-highest cancer-related mortality rate in the world because most patients are diagnosed at an intermediate to advanced stage when surgery is not suitable. Transcatheter arterial chemoembolization (TACE) is currently considered a first-line therapy for unresectable HCC (uHCC), while the efficacy of TACE alone for uHCC patients still needs to be improved. Anlotinib has shown survival benefits in the treatment of uHCC as a kind of novel tyrosine kinase inhibitors (TKIs) in previous studies. Therefore, we aimed to compare clinical outcomes of TACE combined with anlotinib versus TACE monotherapy in patients with uHCC associated with hepatitis B virus (HBV). Methods: We retrospectively collected the data of 96 uHCC patients associated with hepatitis B virus who received either TACE only (TO group; n = 64) or anlotinib combined with TACE (TA group; n = 32) between January 2017 to January 2021. The clinical outcomes including overall survival (OS), progression-free survival (PFS), and tumor response according to mRECIST and RECIST 1.1 were compared between the two groups. Adverse events (AEs) were analyzed to assess the safety profiles. Results: The median OS in the TA group was 17.6 months (95%CI, 11.3 to 24.3) versus 9.4 months (95% CI, 7.8 to 16.3) in the TO group (hazard ratio, 0.59; 95% CI, 0.39 to 0.90; p= 0.018). The median PFS was also significant longer in the TA group (6.7 vs. 3.8months; hazard ratio, 0.46; p&lt; 0.001). Additionally, the objective response rate (ORR) and disease control rate (DCR) numerically increased in the TA group (mRECIST: ORR 65.6% vs. 46.9%, p= 0.064; DCR 90.6% vs. 85.9%, p= 0.382. RECIST 1.1: ORR 46.9% vs. 15.6%, p= 0.001; DCR 90.6% vs. 85.9%, p= 0.382; respectively). No treatment-related mortality occurred. The most common AEs included elevated transaminases (56.3%), decreased appetite (46.9%) and abdominal pain (37.5%) in TA group. Though the incidence rate of grade 3/4 was higher in TA group, all of them were acceptable and controllable. Conclusions: Anlotinib combined with TACE may significantly improve outcomes for uHCC patients associated with hepatitis B virus comparing with TACE monotherapy with a controllable safety profile. Randomized controlled trials with a large sample are warranted to further validate the efficacy.
Efficacy and safety of IBI110 in combination with sintilimab in first-line advanced HER2-negative gastric cancer or gastroesophageal junction cancer: Updated results from a phase Ib study.
Authors: Chenyu Mao, Jiong Qian, Yuan Gao, Ying Liu, Tao Zhang, Jiuwei Cui, Yuling Chen, Haonan Chen, Li Zhao, Hongli Wang, Nong Xu
Journal: Journal of Clinical Oncology (2023)

2576 Background: Sintilimab plus oxaliplatin and capecitabine (XELOX) has become the standard of care in patients (pts) with untreated advanced, recurrent, or metastatic gastric or gastroesophageal junction adenocarcinoma (G/GEJ AC) in China. Dual inhibition of PD-1 and lymphocyte-activation gene 3 (LAG-3) may further improve anti-tumor effect. The preliminary safety and efficacy data of IBI110 plus sintilimab and XELOX in pts with first-line G/GEJ AC were previously presented (Chenyu Mao et al. ASCO 2022). Here, we presented updated safety and efficacy results of this study. Methods: This phase Ib study enrolled patients with previously untreated, unresectable, locally advanced or recurrent/metastatic HER2-negative GC/GEJ AC. Pts received IBI110 200mg IV Q3W and sintilimab 200mg IV Q3W plus XELOX (oxaliplatin 130 mg/m2 Q3W and capecitabine 1000mg mg/m2/time twice daily [BID]) until disease progression, unacceptable toxicity or death. The primary objectives were to evaluate the safety, tolerability, and efficacy of the combination therapy per RECIST v1.1. Results: As of data cutoff January 9 th 2023, 17 pts were assessed as evaluable (median age: 61 years; ECOG PS=1: 14 pts; all gastric cancer). All pts (17/17, 100%) experienced treatment-related adverse events (TRAEs) of any grade, and the most commonly TRAEs were neutrophil count decreased (64.7%), white blood cell count decreased (52.9%), platelet count decreased (52.9%). Grade ≥ 3 TRAEs occurred in 11 pts (64.7%), the most frequent grade ≥ 3 TRAEs were consistent with TRAEs of any grade. Investigator-assessed immune-mediated adverse events (irAEs) occurred in 10 pts (58.8%). Grade ≥ 3 irAEs occurred in 3 pts (17.6%), all led to discontinuation. No treatment-related death occurred. As data cutoff, among 17 efficacy-evaluable pts, the unconfirmed and confirmed objective response rate (ORR) were 88.2% (95% CI, 63.6-98.5) and 64.7% (95% CI, 38.3-85.8), respectively. The disease control rate (DCR) was 94.1% (95% CI, 71.3-99.9). With a median follow up of 13.1 months (95% CI, 7.1-NC), the median duration of response (DoR) and progression-free survival (PFS) were 11.6 months (95% CI, 2.5-14.4) and 12.9 months (95% CI, 3.8-15.8), respectively. The median overall survival (OS) was not reached, and the 12-months OS rate was 70.6% (95% CI, 43.1-86.6). Conclusions: IBI110 in combination with sintilimab and XELOX demonstrated manageable safety and encouraging efficacy results in patients with first-line gastric adenocarcinoma. This is the first positive trial to show clinical benefits of a LAG3 plus PD-1 inhibitor combined with chemotherapy for this population. Clinical trial information: NCT04085185 .
Marketing approvals for cell and gene therapy products in oncology: Current review of EMA and FDA approvals.
Authors: Rehma Chandaria, Kumar Sripathirathan, Yun Jeong Song, Chris A. Learn
Journal: Journal of Clinical Oncology (2023)

e15189 Background: Cell and gene therapies (CGT) are emerging as potentially game-changing treatments for relapsing and refractory cancer. To date, there are 9 CGTs approved for different cancers across the US and EU, majority focused on autologous CAR-T cell therapies for hematological cancers. In addition, there are ~1500 CGTs in preclinical and clinical development for treatment of cancers utilizing diverse approaches. The risks involved with CGTs differ from small molecule and biologics, and therefore the data required to demonstrate their safety are also different. To get an insight into what regulatory agencies are looking for demonstrating safety for anticancer CGTs, we analyzed the supporting nonclinical studies for the currently approved therapies. Methods: We reviewed of the European Public Assessment Reports (EPAR) and FDA Summary Basis for Approval (SBA) documents for the 9 approved anticancer CGTs. In particular, we looked into approaches that were accepted by the regulatory agencies and the justification provided. Results: Of the 9 approved CGTs included in the review, there were 6 autologous CAR-T cell therapies for the treatment of different hematological malignancies, 1 PBMC-based cell therapy for prostate cancer, 1 gene therapy treatment for bladder cancer, and 1 oncolytic virus for melanoma. Of the different cell therapies, only for Carvykti was a non-human primate study conducted with autologous CAR-T cells. The absence of toxicity studies for the other cell therapies was justified by the lack of relevant animal models since autologous human cells do not work in immune competent animals. Safety data was gathered along with pharmacology studies and clinical studies. As stated in ICH guideline S9, genotoxicity and carcinogenicity studies are not essential to support clinical trials for therapeutics intended to treat patients with advanced cancer. However, there is a theoretical risk of insertional mutagenesis with gene therapies. This was addressed with the approved gene therapies using studies for integration site analysis and IL-2 independent growth, together with review of published literature and clinical data. Conclusions: The risks associated with each cell and gene therapy are unique. As the science continues to evolve, together with new technologies and approaches, existing regulatory guidance may not cover the nonclinical study requirements for all products. It is therefore crucial for drug developers to take a risk-based approach in determining the need for appropriate nonclinical safety studies. The application of 3Rs to reduce animal use is widely encouraged and therefore regulatory agencies accept lack of non-relevant animal models as well as other science-based justifications for not conducting conventional animal studies.
Oncology patients through the eyes of their physicians.
Authors: Riham H. AbdelAziz, Marwa Abdelsalam, Saeed Shabaan
Journal: Journal of Clinical Oncology (2023)

e18757 Background: There is a continuous need for optimizing and rationalizing cancer care according to national and international guidelines. The aim of the survey is exploring the thoughts and expectations of oncologists worldwide regarding their patients' management and prognosis and the factors affecting these expectations. This survey shed light on the oncologists' side of the relationship with their patients, which is often ignored. Methods: This is an observational cross-sectional study via an online pre-tested self-administered survey, targeting subspecialties of Oncologists across the world. Results: Among 929 Oncologists who completed the survey, 50.7% worked at University hospitals. They came from 17, 27, 23 and 14 countries in Africa, Asia and Australia, Europe, and the Americas respectively. Our results showed that, 58.7% thought stage of the disease is the most important factor affecting the prognosis. Additionally, 34.4%, 21.4% and 14.2% agreed that the 2 nd most important factor was Performance status, stage of the disease, and disease pathology and immunohistochemistry respectively. Also 63% agreed that targeted therapy improves their expectations of the outcomes in eligible patients. While, 56% agreed that Immunotherapy improves their expectations. Only 42.3% indicated that they always inform patients of the detailed management plan and only 20.7% agreed that they always inform advanced cases about their incurable disease. Moreover, 52% usually expect the patients to fully understand the detailed management plan, but only 7% always expect that. The main factor affecting this is the patients’ education level as indicated by 76% of the respondents. The 2 nd leading cause is that patients usually have some degree of denial as indicated by 35%, followed by patients’ unrealistic expectations as indicated by 30% of oncologists. Results also showed that 63.5% always inform their patients about all adverse events of their therapy directly, and 59% agreed that patients usually accept them, but only 6.5% indicated that patients always accept them. The fear of death or possible disabilities are the main factors causing some patients to reject these adverse events as indicated by 52%, while 31% thought fear of the looming social or financial difficulties is the main cause. The majority agreed that patients are either always (33%) or usually (46.9%) open to their case being discussed in Multidisciplinary clinics. Contrarily, only 5.3% indicated patients are always open to being referred to Psychiatrists. The majority agreed that patients are open to being referred to nutritionists or non-oncology physicians. However, only 19% and 7% agreed that patients are always open to being referred to Palliative care and Hospice respectively. Conclusions: The survey shows that oncologists worldwide have consistent evidence-based prognosis. Contrary to that, it shows widely varying perceptions regarding the patients’ reactions, due to variable factors.
Plasma lipidomic profiling of chemotherapy-induced peripheral neuropathy.
Authors: Nicole Yeung, Hui-Ming Lin, Hannah Timmins, Tiffany Li, David Goldstein, Michael Friedlander, Michelle L. Harrison, Kate Lynette Mahon, Peter Meikle, Susanna Park, Lisa Horvath
Journal: Journal of Clinical Oncology (2023)

3031 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of cytotoxic cancer treatment. This may result in dose reduction (DR) or chemotherapy discontinuation (CD) and ultimately decrease the efficacy of therapy. There is a lack of studies examining the role of lipids in relation to CIPN, despite the association of obesity with worse CIPN, and hyperlipidaemia with diabetic neuropathy. The aim of this study is to determine if circulating lipids are associated with CIPN severity. Methods: Pre-chemotherapy plasma samples from 137 patients with CIPN from docetaxel or paclitaxel-based treatment underwent lipidomic analysis (788 lipids). CIPN severity was measured using the neurological grading scale Total Neuropathy Score-clinical version (TNSc score; John Hopkins University) and patient-reported outcome measure EORTC QLQ-CIPN20. The association of baseline lipid levels with severe CIPN, as defined by high TNSc and CIPN20 scores, was performed using linear modelling (LIMMA). Baseline lipids associated with shorter time to dose reduction (DR) or chemotherapy discontinuation (CD) due to CIPN was determined by Cox regression, with adjustment for body mass index (BMI), age and diabetes. Lipid profiles were identified using latent class analysis (LCA) of significant lipids from the Cox regression. Results: Higher TNSc or CIPN20 scores were associated with 107 and 43 lipid species respectively (LIMMA p&lt;0.05), of which only 3 species were in common. Triacylglycerols (TG) represented a significant proportion of lipids with elevated levels associated with higher TNSc (32.5%) or CIPN20 (9.1%) scores (Fisher’s exact test p&lt;0.001). 70 lipid species were associated with shorter time to DR/CD (Cox regression p&lt;0.05), which included 15 TG with higher levels associated with shorter time to DR/CD. Unsupervised LCA identified a specific lipid profile associated with worse CIPN [Hazard ratio 2.61 (95% CI 1.40 – 4.84, p=0.002)]. This lipid profile also had higher levels of TG (t-test p&lt;0.05). The high risk CIPN lipid profile was independently associated with shorter time to DR/CD when modelled with clinical factors (diabetes, age, BMI or prior numbness/tingling; Cox regression p&lt;0.006); however, these clinical factors were not associated with time to DR/CD in the multivariable models (p&gt;0.08). Conclusions: Higher levels of baseline plasma TG are associated with increased CIPN severity and shorter time to DR/CD in taxane-treated patients. These findings are consistent with other reports regarding the association of hyperlipidaemia with neuropathy. Further research is required to determine if TG-lowering medication can reduce the risk of CIPN development.
FOLFOXIRI plus bevacizumab and atezolizumab as upfront treatment of unresectable metastatic colorectal cancer (mCRC): Updated and overall survival results of the phase II randomized AtezoTRIBE study.
Authors: Carlotta Antoniotti, Daniele Rossini, Filippo Pietrantonio, Lisa Salvatore, Federica Marmorino, Margherita Ambrosini, Sara Lonardi, Maria Bensi, Roberto Moretto, Stefano Tamberi, Ilaria Toma, Alessandro Passardi, Maria Caterina De Grandis, Veronica Conca, Federica Palermo, Alessandro Cappetta, Aurelie Catteau, Luca Boni, Jérôme Galon, Chiara Cremolini
Journal: Journal of Clinical Oncology (2023)

3500 Background: AtezoTRIBE (NCT03721653) is a phase II randomized trial in which unresectable mCRC pts were randomized 1:2 to 1 st -line FOLFOXIRI/bev [arm A] or FOLFOXIRI/bev/atezo [arm B]. Adding atezo to FOLFOXIRI/bev was safe and improved PFS (primary endpoint), with a modest benefit also among pts with pMMR tumors. Subgroup analyses suggest that TMB and Immunoscore IC (IS IC) -an IHC biomarker measuring CD8 and PD-L1 cell densities and their proximity- may identify pts with pMMR tumors deriving benefit from adding atezo to FOLFOXIRI/bev. Methods: The study had 85% power to detect a HR for PFS (time from randomization to 1 st PD or death [PD1]) of .66 in favor of arm B with 1-sided α error of .10. Secondary endpoints included PFS2 (time from randomization to PD on any treatment given after PD1 or death [PD2]), 2 nd PFS (time from PD1 to PD2), and OS. MMR, TMB, IS IC were correlated to clinical outcome. Results: 218 pts (arm A/B:73/145) were enrolled. Main pts’ characteristics were right-sided 44%/45%, RAS mut 71%/74%, BRAF mut 14%/8%, dMMR 7%/6%, high TMB 10%/12%, high IS IC 32%/32%. At a median follow-up of 37.0 mos, 175 (80%, arm A/B: 64/111) PD1, 150 (69%, arm A/B: 53/97) PD2, and 118 (54%, arm A/B: 43/75) OS events were collected. Out of 175 pts with a PD1 event, 135 (77%, arm A/B:50/85) received a subsequent treatment; among them, 121 pts (arm A/B: 43/78) had a PD2 event. PFS, PFS2, 2 nd PFS and OS results in the intention-to-treat (ITT) population and the pMMR group are listed in the Table. In the ITT population, significant interactions between treatment and MMR status (P int .011), TMB (P int .008), and IS IC (P int .037) were reported in terms of PFS. Only IS IC was associated with a differential OS benefit (P int .065), with pts bearing IS IC-high tumors deriving benefit from adding atezo (HR 0.43, 95%CI 0.19-1.00), differently than those with IS IC-low tumors (HR 1.09, 95%CI 0.65-1.83). In the pMMR group, significant interactions between treatment and TMB and IS IC were reported in terms of PFS (P int .016 and .051, respectively) and OS (P int .043 and .063, respectively). Pts bearing IS IC-high tumors derived higher OS benefit from adding atezo (HR 0.44, 95%CI 0.19-1.03), than those with IS IC-low tumors (HR 1.15, 95% CI 0.67-1.97). Conclusions: Pts with IS IC-high and/or TMB high pMMR mCRC seem to derive a survival benefit from adding atezo to FOLFOXIRI/bev as upfront treatment. These findings deserve confirmation in a properly designed phase III trial. Clinical trial information: NCT03721653 . [Table: see text]
Use of direct oral anticoagulants (DOACs) in oncology: A phase IV study on impact of edoxaban treatment in Italian patients with cancer with venous thromboembolism during antineoplastic therapy (EDOI trial, GOIRC 05-2018).
Authors: Filippo Giovanardi, Massimo Di Maio, Erika Gervasi, Alessandra Romagnani, Angela Damato, Marcello Tiseo, Stefano Tamberi, Vincenzo Montesarchio, Salvatore Grisanti, Marco Platania, Annamaria Catino, Rodolfo Passalacqua, Andrea Vincent Bonetti, Giovanni Vicario, Silvia Finotto, Fabio Gelsomino, Carmine Pinto
Journal: Journal of Clinical Oncology (2023)

6564 Background: The EDOI Study (EUDRACT 2018-003833-14) was designed to evaluate venous thromboembolism (VTE), a common complication of cancer and cancer therapy. VTE contributes to mortality and morbidity, and may interfere with therapy. When drafting the protocol, the standard treatment for VTE consisted of low-molecular weight heparin followed by vitamin K antagonists. DOACs are as effective as vitamin K antagonists in the treatment of VTE. Edoxaban has been confirmed to be effective and safe in the treatment of VTE. Adverse events (AEs) associated with DOACs can delay or interfere with chemotherapy; to date, data regarding the impact of Edoxaban treatment on cancer treatment AEs are scanty. Methods: In this multicentric, phase IV study, patients receiving an antineoplastic treatment (and candidates for at least 3 additional months of treatment) and diagnosed with VTE, received Edoxaban as per clinical practice. Patients received between 6 and 12 months of Edoxaban and were evaluated at baseline and after 1, 3 and 6 months. Primary endpoint was the impact of Edoxaban-related AEs on antineoplastic therapy, defined as delays/interruptions/reductions due to adverse drug reactions (ADR) related to Edoxaban (bleeding, hepatobiliary toxicity, renal toxicity, anemia, hypersensitivity reactions). As secondary endpoint, we assessed patient-reported outcomes (PROs) during treatment with Edoxaban (health-related quality of life: FACT-G, expectations and satisfaction with anticoagulant treatment: PACT-Q2 and ACTS). For each tool, mean scores at each time point were calculated. Results: One hundred and fifty patients were enrolled, 147 patients were evaluable. The Incidence density rate of antineoplastic therapy delay/interruption/reduction due to ADR related to Edoxaban was 0,8% per person-month (90% CI: [0,4; 1,5%] and 95% CI: [0,4; 1,6%]). For all the patient-reported outcomes, mean scores were maintained at different time points. Conclusions: The results of the study clearly show that the edoxaban treatment is well tolerated and has no relevant impact on the delivery of cancer treatments. Results in terms of quality of life and patients’ satisfaction with anticoagulant treatment are reassuring. Clinical trial information: EUDRACT 2018-003833-14 . [Table: see text]
Quantitative analysis of MMR deficiency in dMMR/MSI high CRC and levels of instability: Implications for ICI therapy of dMMR tumors.
Authors: Marija Staninova Stojovska, Nadica Matevska Geshkovska, Rubens Jovanovic, Katerina Kubelka Sabit, Biljana Angelovska, Nenad Mitrevski, Milco Panovski, Toni Josifovski, Aleksandar J Dimovski
Journal: Journal of Clinical Oncology (2023)

e14650 Background: Mismatch repair deficiency (dMMR) is observed in ~15% of newly diagnosed colorectal cancer (CRC) tumors. It is routinely scored as a qualitative trait (positive or negative) and, if present, is considered a positive predictive marker for immune checkpoint inhibitors (ICI) therapy not only in patients with metastatic CRC (mCRC), but also in patients with other dMMR solid tumors. However, a significant proportion of these patients experience failure of ICI treatment and no predictive biomarkers exist that can identify such patients. Methods: A total of 42 patients with dMMR tumors were selected for analysis, of which 26 had a hereditary Lynch Syndrome (LS) with known pathogenic variants in the MMR genes (MLH1, MSH2, MSH6, PMS2) and 16 had sporadic dMMR CRC due to epigenetic silencing of the MLH1 gene. All tumors were also analyzed for the presence of the RAS/RAF pathway mutations. MMR deficiency was initially evaluated by two standard methods: immunohistochemistry (IHC) and by microsatellite instability (MSI)-PCR on DNA isolated from FFPE tissues with &gt; 50% tumor content. Subsequently, whole exome sequencing (WES) with a mean depth of &gt;150 reads was performed on the same DNA samples using the NovaSeq 6000 platform. NGS data were analyzed using the MSI sensor package which evaluates &gt;2000 sites with mono- to pentanucleotide repeats. Each site was scored as NGS-MSI unstable if it contained at least 20% unstable reads. The percent of unstable loci was referred to as NGS-MSI level. All tumors with &gt;3.5% of unstable loci were classified as NGS-MSI positive. Results: A considerable variability in the NGS-MSI levels ranging from 1.5 – 76% was observed in patients that were initially classified as dMMR/PCR-MSI high. CRC tumors of LS patients with deleterious MMR gene mutations and the majority of patients with sporadic CRC due to MLH1 gene promotor methylation had &gt;50% unstable loci. In contrast, more than 1/3 of patients with isolated loss of MSH6 and PMS2 detected by IHC had substantially lower NGS-MSI levels of 1.5 to 12%. These patients had a negative PCR-MSI result and their molecular defects were primarily missense mutations in MSH6 and PMS2 genes. It is interesting to note that a low NGS-MSI score (&lt;10%) was also detected in patients with sporadic CRC that had MLH1 gene promotor methylation but also the BRAF V600E mutation. Conclusions: Our results indicate that dMMR/MSI-H tumors exhibit a high variability in the percentage of unstable loci that correlates with particular molecular backgrounds. A larger study on different types of tumors is warranted, especially in the context of the efficacy of ICI therapy in patients with MMR tumors classified by qualitative MMR/MSI assays.